Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM). Common mutations include MYD88 (95%-97%), as well as CXCR4 (30%-40%), ARID1A (17%), and CD79B (8%-15%), which are typically found in MYD88-mutated patients. The genomic findings provide important insights into the pathogenesis, prognostication, and treatment outcome in WM. We discuss the genomic landscape of WM, and the impact of underlying genomics on disease presentation, transcriptional changes, treatment outcome, and overall survival impact.